1. Field of Invention
This invention relates to a method of treating muscle tension, muscle spasticity and anxiety in living animals, including humans, with 3-aryloxy and 3-arylthioazetidinecarboxamides, certain of which are novel, and a novel process for preparing 3-phenoxy-1-azetidinecarbonylchloride chemical intermediates.
2. Information Disclosure Statement
Certain of the compounds useful in the method of the present invention are disclosed in U.S. Pat. No. 4,226,861 as having anticonvulsant activity and use in treating epilepsy having the formula: ##STR2## wherein R is loweralkyl and R.sup.1 is hydrogen, aminocarbonyl or trifluoromethyl.
Certain other of the compounds useful in the present invention are disclosed in U.S. Pat. No. 4,571,393, as having anticonvulsant activity and having the formula: ##STR3## wherein R.sup.1 =H, F, loweralkyl, loweralkoxy, trifluoromethyl, acetyl, or aminocarbonyl. A U.S. application from an earlier parent U.S. application Ser. No. 409,476 filed Aug. 19, 1982, now abandoned, which application stated that the compounds of U.S. Pat. No. 4,226,861, mentioned above, have muscle relaxant property and based on another less reliable test stated that the compounds in U.S. application Ser. No. 409,476 do not have muscle relaxant activity at an effective anticonvulsant dosage. The subject matter of U.S. application Ser. No. 409,476 subsequently was published in European patent application 102-194-A on Mar. 7, 1984.
A U.S. application Ser. No. 706,621 filed on Feb. 28, 1985, discloses a group of novel compounds within the generic formula of the present invention and others wherein R.sup.1 and R.sup.2 encompass aminoloweralkyl radicals as having anticonvulsant activity and methods and compositions for treating epilepsy.
One novel aspect of the present invention is a process for preparing 1-chlorocarbonyl-3-aryloxyazetidine intermediates from phosgene and 1-diphenylmethyl or 1-(1-phenylethyl)-3-aryloxyazetidines. U.S. Pat. No. 4,547,514 discloses preparation of 1-chlorocarbonyl-3-aryloxypyrrolidines by reaction of 1-benzyl-3-aryloxypyrrolidines and phosgene. However, analogous application of the use of the 1-benzyl group in corresponding preparation of 1-chlorocarbonyl azetidine compounds there are two major considerations: 1) synthesis of 1-benzyl-3-phenoxyazetidines is highly impractical, and 2) by-product benzyl chloride is extremely difficult to separate and any residual benzyl chloride reacts with amidating agents. Prior to the present invention, displacement of 1-diphenylmethyl or 1-(1-phenylethyl) groups of azetidine compounds was unknown and these groups were thought to be too bulky for displacement by phosgene.
U.S. Pat. No. 4,031,221 discloses reaction of 1-benzyl and 1-diphenylmethyl-3-phenoxy heterocyclic amines with alkyl or phenylchloroformate to prepare 1-alkylcarbonyl or 1-phenylcarbonyl derivatives, in particular, 1-diphenylmethyl-3-(4-trifluorophenoxy)azetidine with phenylchloroformate to give 1-phenoxycarbonyl-3-(p-fluorophenoxy) azetidine. Such phenoxycarbonyl compounds do not, of course, react directly with amines as do the chlorocarbonyl intermediates prepared by the novel process of this invention. Furthermore, the foregoing reaction with the chloroformates leads to substantial azetidine ring opening not seen in the phosgene reaction and the phosgene reaction occurs at a lower temperature in a short time.